ArticleThe FEBS journal2015
Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors.
Article in The FEBS journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Discovery of Pyrroloquinazoline-1,3-diamines as Dual-function Insecticide Candidates Targeting β-N-acetyl-D-hexosaminidase.Current medicinal chemistry · 2026Article
- Development of antibacterial compounds that constrain evolutionary pathways to resistance.eLife · 2021Article
- New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action.Antibiotics (Basel, Switzerland) · 2021Article
- FRAGSITE: A Fragment-Based Approach for Virtual Ligand Screening.Journal of chemical information and modeling · 2021Article
- Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential.Oncogene · 2021Review
- Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.ACS infectious diseases · 2021Article
- Multistep Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity.Journal of medicinal chemistry · 2020Article
- Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors.The Journal of antibiotics · 2020Review
- Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs.Molecules (Basel, Switzerland) · 2019Article
- Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs.Medicinal research reviews · 2019Review
- The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release.Communications biology · 2018Article
- Structural and Dynamics Perspectives on the Binding of Substrate and Inhibitors in Mycobacterium tuberculosis DHFR.Scientia pharmaceutica · 2017Article
- Pocket detection and interaction-weighted ligand-similarity search yields novel high-affinity binders for Myocilin-OLF, a protein implicated in glaucoma.Bioorganic & medicinal chemistry letters · 2017Article
- Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.ACS chemical biology · 2017Article
- Novel small molecule binders of human N-glycanase 1, a key player in the endoplasmic reticulum associated degradation pathway.Bioorganic & medicinal chemistry · 2016Article
- Catalytic and substrate promiscuity: distinct multiple chemistries catalysed by the phosphatase domain of receptor protein tyrosine phosphatase.The Biochemical journal · 2016Article
- Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase.European journal of medicinal chemistry · 2015Article
- PoLi: A Virtual Screening Pipeline Based on Template Pocket and Ligand Similarity.Journal of chemical information and modeling · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Dihydrofolate reductase (DHFR) is a pivotal enzyme involved in the de novo pathway of purine synthesis, and hence, represents an attractive target to disrupt systems that require rapid DNA turnover. The enzyme acquires resistance to available drugs by various molecular mechanisms, which necessitates the continuous discovery of novel antifolates. Previously, we identified a set of novel molecules that showed binding to E. coli DHFR by means of a thermal shift without establishing whether they inhibited the enzyme. Here, we show that a fraction of those molecules represent potent and novel inhibitors of DHFR activity. 7-[(4-aminophenyl)methyl]-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine, a molecule with no reported inhibition of DHFR, potently inhibits the enzyme with a Ki value of 7.42 ± 0.92 nm by competitive displacement of the substrate dihydrofolic acid. It shows uncompetitive inhibition vis-à-vis NADPH, indicating that the inhibitor has markedly increased affinity for the NADPH-bound form of the enzyme. Further, we demonstrate that the mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model. By contrast, mechanistic characterization of the parent molecule 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine shows that lack of (4-aminophenyl)-methyl group at the seventh position abolishes the slow onset of inhibition. This finding provides novel insights into the role of substitutions on inhibitors of E. coli DHFR and represents the first detailed kinetic investigation of a novel diaminopyrroloquinazoline derivative on a prokaryotic DHFR. Furthermore, marked differences in the potency of inhibition for E. coli and human DHFR makes this molecule a promising candidate for development as an antibiotic.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.